The retina is a thin layer of light-sensitive tissue that lines the inside wall of the back of the eye. When light enters the eye, it is focused by the cornea and the lens onto the retina. The retina then transforms the light images into electrical impulses that are sent to the brain through the optic nerve.
The macula is a very small area of the retina responsible for central vision and color vision. The macula allows us to read, drive, and perform detailed work. Surrounding the macula is the peripheral retina which is responsible for side vision and night vision. Macular degeneration is damage or breakdown of the macula, underlying tissue, or adjacent tissue. Macular degeneration is the leading cause of decreased visual acuity and impairment of reading and fine "close-up" vision. Age-related macular degeneration (ARMD) is the most common cause of legal blindness in the elderly.
The most common form of macular degeneration is called "dry" or involutional macular degeneration and results from the thinning of vascular and other structural or nutritional tissues underlying the retina in the macular region. A more severe form is termed "wet" or exudative macular degeneration. In this form, blood vessels in the choroidal layer (a layer underneath the retina and providing nourishment to the retina) break through a thin protective layer between the two tissues. These blood vessels may grow abnormally directly beneath the retina in a rapid uncontrolled fashion, resulting in oozing, bleeding, or eventually scar tissue formation in the macula which leads to severe loss of central vision. This process is termed choroidal neovascularization (CNV).
CNV is a condition that has a poor prognosis; effective treatment using thermal laser photocoagulation relies upon lesion detection and resultant mapping of the borders. Angiography is used to detect leakage from the offending vessels but often CNV is larger than indicated by conventional angiograms since the vessels are large, have an ill-defined bed, protrude below into the retina and can associate with pigmented epithelium.
Neovascularization results in visual loss in other eye diseases including neovascular glaucoma, ocular histoplasmosis syndrome, myopia, diabetes, pterygium, and infectious and inflammatory diseases. In histoplasmosis syndrome, a series of events occur in the choroidal layer of the inside lining of the back of the eye resulting in localized inflammation of the choroid and consequent scarring with loss of function of the involved retina and production of a blind spot (scotoma). In some cases, the choroid layer is provoked to produce new blood vessels that are much more fragile than normal blood vessels. They have a tendency to bleed with additional scarring, and loss of function of the overlying retina. Diabetic retinopathy involves retinal rather than choroidal blood vessels resulting in hemorrhages, vascular irregularities, and whitish exudates. Retinal neovascularization may occur in the most severe forms.
Current diagnosis of ocular disorders often includes use of a dye such as fluorescein or indocyanine green in an angiogram. Fluorescein is a low molecular weight molecule that rapidly leaks from vessels, however, due to its low absorption and emission wavelengths and due to autofluorescence, only superficial morphology can be imaged; subretinal hemorrhage blocks the detection of the underlying chorioretinal vasculature. In contrast, ICG, having an absorption band at 805 nm and fluorescence at 835 nm, is able to image deeper choroidal vessels better than fluorescein due to spectral differences and also due to its longer retainment in the diseased vasculature, possibly in association with albumin. In this procedure, the dye is injected into the blood stream through a vein in the arm. Special filters are placed in the light path, and in front of the film, to permit the fluorescent dye to be seen as it passes through the vessels in the retina Pictures of the vascular anatomy are taken of the retina and macula as the dye passes through the blood vessels of the back of the eye. Vascular occlusions or leakage of dye generally indicates abnormal vasculature, however, a problem with fluorescein is that of leakage. Optical coherence tomography is another technique that uses noncontact imaging and provides high-depth resolution in cross-sectional tomographs of the retina.
Current treatment of neovascularization relies on ablation of blood vessels using thermal laser photocoagulation. However, such treatment is nonselective, requires thermal destruction of the tissue, and is accompanied by full-thickness retinal damage, as well as damage to medium and large choroidal vessels. Further, the patient is left with an atrophic scar and visual scotoma. Moreover, recurrences are common, and the prognosis for the patient's condition is poor.
Developing strategies have sought more selective closure of the blood vessels to preserve the overlying neurosensory retina. One such strategy is photodynamic therapy (PDT), a treatment technique that uses a photosensitizing dye and non-damaging light corresponding to the sensitizer's absorption profile to produce cytotoxic materials, such as singlet oxygen, from benign precursors when irradiated in the presence of oxygen.
Other reactive species such as superoxide, hydroperoxyl, or hydroxyl radicals may be involved in the consequent irreversible damage to biological components. At the doses used, neither the light nor the drug has any independent activity against the target.
The effectiveness of PDT is predicated on three additional factors: i) The photosensitive dyes used in PDT preferably have the ability to localize at the treatment site as opposed to surrounding tissue. ii) The high reactivity and short lifetime of activated oxygen means that it has a very short range (.about.0.1 .mu.m) and is unlikely to escape from the region in which it is produced; cytotoxicity is therefore restricted to the precise region of photoactivated drug. iii) Developments in light delivery, such as lasers, light emitting diodes, and fiber optics, allow a beam of intense, non-damaging, light to be delivered accurately to many parts of the body. For a review of photodynamic therapy, see U.S. Pat. No. 5,252,720 (incorporated by reference herein).
Photodynamic therapy of conditions in the eye characterized by neovascularization has been attempted using conventional porphyrin derivatives such as hematoporphyrin derivative (dihematoporphyrin ether), PHOTOFRIN.RTM. porfimer sodium, and tin ethyl etiopurpurin. Problems have been encountered in this context due to interference from eye pigments, as described in U.S. Pat. No. 5,576,013 to Williams, et al. for example. In addition, phthalocyanine and benzoporphyrin derivatives have been used in photodynamic treatment. PCT publication WO 95/24930 and Miller et al., (Archives of Ophthalmology, June, 1995) relate to treatment of eye conditions characterized by unwanted neovasculature comprising administering a green porphyrin to the neovasculature and irradiating the neovasculature with light having a wavelength of 550-695 nm. U.S. Pat. No. 5,166,197 and 5,484,778 relate to phthalocyanine derivatives reportedly useful for macular degeneration. Asrani and Zeimer (British Journal of Ophthalmology, 1995, 79:766-770) relate to photoocclusion of ocular vessels using a phthalocyanine encapsulated in heat-sensitive liposomes. Levy (Semin. Oncol. 1994, 21/6, suppl. 15 (4-10)) relates to photodynamic therapy with porfimer sodium (PHOTOFRIN.RTM., requiring light of 630 nm and causing cutaneous photosensitivity that may last for up to 6 weeks), and benzoporphyrin derivative (BPD verteporfin, causing cutaneous photosensitivity of a few days). Lin et al. (IOVS 34:1303 Abstract 2953, 1993) relate to the photodynamic occlusion of choroidal vessels using benzoporphyrin derivative BPD-MA. Baumal et al. (Invest. OphthalmoL Vis. Sci. 37/3:S122 (abstract) 1996) relates to PDT of experimental choriodal neovascularization with tin ethyl etiopurpurin (SnET2) and 665 nm irradiation. BPD and SnET2 are insoluble in aqueous solutions and require hydrophobic vehicles for administration. Further limitations of prior art photosensitizers include inadequate light penetration through hemorraghic and pigmented tissue, systenic cutaneous photosensitivity, lack of selectivity, normal tissue damage, and reopening of diseased vessels. Hydrophobic vehicle solubilizers require clearance time prior to irradiation. Bolus injection and instantaneous illumination cannot be performed.
Texaphyrins are aromatic pentadentate macrocyclic "expanded porphyrins" useful as MRI contrast agents, as radiosensitizers, as chemosensitizers, and in photodynamic therapy. Texaphyrin is considered as being an aromatic benzannulene containing both 18.pi.- and 22.pi.-electron delocalization pathways. Texaphyrin molecules absorb strongly in the tissue-transparent 700-900 nm range, and they exhibit inherent selective uptake or biolocalization in certain tissues, particularly regions such as, for example, liver, atheroma or tumor tissue. Texaphyrins have exhibited significant tumor selectivity as detected by magnetic resonance imaging and fluorescence detection. Texaphyrins and water-soluble texaphyrins, method of preparation and various uses have been described in U.S. Pat. Nos. 4,935,498; 5,162,509; 5,252,720; 5,256,399; 5,272,142; 5,292,414; 5,369,101; 5,432,171; 5,439,570; 5,451,576; 5,457,183; 5,475,104; 5,504,205; 5,525,325; 5,559,207; 5,565,552; 5,567,687; 5,569,759; 5,580,543; 5,583,220; 5,587,371; 5,587,463; 5,591,422; 5,594,136; 5,595,726; 5,599,923; 5,599,928; 5,601,802; 5,607,924; and 5,622,946; PCT publications WO 90/10633; 94/29316; 95/10307; 95/21845; 96/09315; 96/38461; 96/40253; 97/26915; and 97/35617; PCT application application PCT/US97/09501 published as WO 97/46262; allowed U.S. patent application Ser. No. 08/458,347, issued as U.S. Pat. No. 5,798,491; Ser. No. 08/484,551, issued as U.S. Pat. No. 5,714,328; and Ser. No. 08/591,318, issued as U.S. Pat. No. 5,776,925; and U.S. patent application Ser. No. 08/763,451 converted to Ser. No. 60/093,058, now abandoned; Ser. No. 08/903,099, issued as U.S. Pat. No. 6,022,526; and Ser. No. 08/914,272, issued as U.S. Pat. No. 5,775,339; each patent, publication, and application is incorporated herein by reference.
The present invention provides texaphyrins for ocular diagnosis and therapy. The use of texaphyrins circumvents problems seen in prior art methods, in part, because of the dual wavelengths for absorption of light, solubility in aqueous solutions, rapid clearance, use of a bolus injection, and the provision of a single agent for visualization and treatment.